Cell-Cell Interactions and the Regulation of Testis Function

Regulatory interactions have been shown to occur between all the testicular cell types considered. The paracrine factors mediating these interactions generally influence either cellular growth or differentiation. The regulation of cellular growth is essential in the developing testis and is required for the maintenance of spermatogenesis in the adult testis. The rapid rate of germinal cell proliferation and the continuous but slowed growth of the peritubular cells and Leydig cells requires the presence of specific growth factors in the adult. Therefore, cell-cell interactions have evolved that involve growth factors such as IGF, TGF-alpha, TGF-beta and NGF. Other growth factors such as FGF or less characterized components like the seminiferous growth factor (SGF) also may be involved in the paracrine regulation of testis cell growth. An alternate cellular parameter to cell growth to consider is the regulation of cellular function and differentiation. A number of endocrine agents and locally produced paracrine factors have been shown to control and maintain testis cell function and differentiation. Cell-cell interactions mediated by factors such as androgens, POMC peptides, and PModS are all primarily directed at the regulation of cellular differentiation. Therefore, the agents which mediate cell-cell interactions in the testis can generally be categorized into factors that regulate cell growth or those which influence cellular differentiation. The specific cell-cell interactions identified will likely be the first of a large number of cellular interactions yet to be investigated. Although a number of potentially important cell-cell interactions have been identified, future research will require the elucidation of the in vivo physiological significance of these interactions. The existence of different cell types and potential cell-cell interactions in a tissue implies that the actions of an endocrine agent on a tissue will not simply involve a single hormone and single cell. The endocrine regulation of testis function will have effects on cell-cell interactions and be affected by local cell-cell interactions. The ability of LH to influence Leydig cell androgen production promotes a cascade of interactions mediated through several cell types to maintain the process of spermatogenesis. FSH actions on Sertoli cells also promote cell-cell interactions that influence germinal cell development, peritubular myoid cell differentiation and Leydig cell function. Therefore, elucidation of the endocrine regulation of testis function requires an understanding of the local cell-cell interactions in the testis

Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegans Bardet-Biedl Syndrome Mutants

Bardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder with clinical presentations including polydactyly, retinopathy, hyperphagia, obesity, short stature, cognitive impairment, and developmental delays. Disruptions of BBS proteins in a variety of organisms impair cilia formation and function and the multi-organ defects of BBS have been attributed to deficiencies in various cilia-associated signaling pathways. In C. elegans, bbs genes are expressed exclusively in the sixty ciliated sensory neurons of these animals and bbs mutants exhibit sensory defects as well as body size, feeding, and metabolic abnormalities. Here we show that in contrast to many other cilia-defective mutants, C. elegans bbs mutants exhibit increased release of dense-core vesicles and organism-wide phenotypes associated with enhanced activities of insulin, neuropeptide, and biogenic amine signaling pathways. We show that the altered body size, feeding, and metabolic abnormalities of bbs mutants can be corrected to wild-type levels by abrogating the enhanced secretion of dense-core vesicles without concomitant correction of ciliary defects. These findings expand the role of BBS proteins to the regulation of dense-core-vesicle exocytosis and suggest that some features of Bardet-Biedl Syndrome may be caused by excessive neuroendocrine secretion

Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report.

Triple-A syndrome (Allgrove syndrome) is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and - occasionally - autonomic instability. Mutations have been found in the AAAS gene on 12q13

Geochemical and Strontium Isotope Characterization of Produced Waters from Marcellus Shale Natural Gas Extraction

Extraction of natural gas by hydraulic fracturing of the Middle Devonian Marcellus Shale, a major gas-bearing unit in the Appalachian Basin, results in significant quantities of produced water containing high total dissolved solids (TDS). We carried out a strontium (Sr) isotope investigation to determine the utility of Sr isotopes in identifying and quantifying the interaction of Marcellus Formation produced waters with other waters in the Appalachian Basin in the event of an accidental release, and to provide information about the source of the dissolved solids. Strontium isotopic ratios of Marcellus produced waters collected over a geographic range of ∼375 km from southwestern to northeastern Pennsylvania define a relatively narrow set of values (εSr SW = +13.8 to +41.6, where εSr SW is the deviation of the 87Sr/86Sr ratio from that of seawater in parts per 104); this isotopic range falls above that of Middle Devonian seawater, and is distinct from most western Pennsylvania acid mine drainage and Upper Devonian Venango Group oil and gas brines. The uniformity of the isotope ratios suggests a basin-wide source of dissolved solids with a component that is more radiogenic than seawater. Mixing models indicate that Sr isotope ratios can be used to sensitively differentiate between Marcellus Formation produced water and other potential sources of TDS into ground or surface waters

Growth Factor Regulation of Testicular Function

The evolution of multicellular organisms required communication between different cells to coordinate tissue function. These cell-cell interactions have become vital for the regulation of cellular function, growth, and differentiation

A phase I/II and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma

This phase I/II study was conducted to determine the maximum recommended dose of pemetrexed when given in combination with a fixed dose of cisplatin, and the efficacy, toxicity and association of 5,10-methylenetetrahydrofolate reductase (MTHFR) variants with this pemetrexed-cisplatin combination, in patients with unresectable, advanced gastric carcinoma. Patients 18-70 years of age, with stage IV disease or post-surgery recurrence, no earlier palliative chemotherapy, 0 or 1 Eastern Cooperative Oncology Group performance status, were included. The cisplatin dose was 75mg/m(2). In phase I, the initial dose of pemetrexed was 600mg/m(2), escalated in 100mg/m(2) increments. In phase II, efficacy, including overall response rate, overall survival, as well as toxicity and MTHFR pharmacogenetics were investigated. Phase I enrolled 16 patients; 700mg/m(2) was defined as pemetrexed recommended dose. Thirteen serious adverse events were reported; the most common grade 3/4 toxicities were haematologic (10 of 13, 76.9%). Phase II enrolled 73 patients, 69 qualified for safety and 68 for efficacy analysis; 65 for pharmacogenomic analysis. Overall response rate was 23.5% (14.1%, 35.4%), disease control rate 55.9%, median overall survival 11.8 months (95% confidence interval, 7.2-18.5 months), progression-free survival 4.9 months (95% confidence interval, 2.8-7.1 months), and median response duration 5.4 months. Patients with MTHFR A1298C variants had median overall survival of 6.6 months, significantly shorter than patients with the wild type (median 18.5 months, P = 0.001). The pemetrexed-cisplatin combination in patients with advanced gastric cancer generates modest efficacy and a manageable toxicity profile. The reduced overall survival in patients with MTHFR A1298C polymorphism variants deserves further investigation. Anti-Cancer Drugs 21: 777-784 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor

Background: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. Objectives: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. Methods: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. Results: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of Conclusion: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.</p